Structural and Functional Analysis of SHP Promoter and Its Transcriptional Response to FXR in Zn-Induced Changes to Lipid Metabolism

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Jun 24

PMID 35742980

Authors

Han Gao

Xing Fan

Qi-Chun Wu

Chuan Chen

Fei Xiao

Kun Wu

Affiliations

Soon will be listed here.

Abstract

Zinc alleviates hepatic lipid deposition, but the transcriptional regulatory mechanisms are still unclear. In this study, we characterized the promoter of an SHP (short heterodimer partner) in a teleost . The binding sites of an FXR (farnesoid X receptor) were predicted by the SHP promoter, indicating that the FXR mediated its transcriptional activity. The site mutagenesis and the EMSA (electrophoretic mobility shift assay) found that the -375/-384 bp FXR site on the SHP promoter was the functional binding locus responsible for the Zn-induced transcriptional activation. A further study of yellow catfish hepatocytes suggested that the activation of the FXR/SHP is responsible for the effect of Zn on the decreasing lipid content. Thus, this study provides direct evidence of the interaction between the FXR and SHP promoter in fish, and accordingly elucidates the potential transcriptional mechanism by which Zn reduces hepatic lipid accumulation.

Citing Articles

FOXO3/Rab7-Mediated Lipophagy and Its Role in Zn-Induced Lipid Metabolism in Yellow Catfish ().

Xiao F, Chen C, Zhang W, Wang J, Wu K Genes (Basel). 2024; 15(3).

PMID: 38540393 PMC: 10969980. DOI: 10.3390/genes15030334.

References

Wu K, Tan X, Xu Y, Chen G, Zhuo M . Functional Analysis of Promoters of Genes in Lipid Metabolism and Their Transcriptional Response to STAT3 under Leptin Signals. Genes (Basel). 2018; 9(7). PMC: 6071087. DOI: 10.3390/genes9070334. View

Roy A, Singer D . Core promoters in transcription: old problem, new insights. Trends Biochem Sci. 2015; 40(3):165-71. PMC: 4340783. DOI: 10.1016/j.tibs.2015.01.007. View

Lee Y, Chanda D, Sim J, Park Y, Choi H . Structure and function of the atypical orphan nuclear receptor small heterodimer partner. Int Rev Cytol. 2007; 261:117-58. DOI: 10.1016/S0074-7696(07)61003-1. View

Ranasinghe P, Wathurapatha W, Ishara M, Jayawardana R, Galappatthy P, Katulanda P . Effects of Zinc supplementation on serum lipids: a systematic review and meta-analysis. Nutr Metab (Lond). 2015; 12:26. PMC: 4523910. DOI: 10.1186/s12986-015-0023-4. View

Wu K, Huang C, Shi X, Chen F, Xu Y, Pan Y . Role and mechanism of the AMPK pathway in waterborne Zn exposure influencing the hepatic energy metabolism of Synechogobius hasta. Sci Rep. 2016; 6:38716. PMC: 5146659. DOI: 10.1038/srep38716. View

Kassam A, Capone J, Rachubinski R . The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes.... Mol Cell Endocrinol. 2001; 176(1-2):49-56. DOI: 10.1016/s0303-7207(01)00475-0. View

Hambidge K, Krebs N . Zinc deficiency: a special challenge. J Nutr. 2007; 137(4):1101-5. DOI: 10.1093/jn/137.4.1101. View

Wu K, Luo Z, Hogstrand C, Chen G, Wei C, Li D . Zn Stimulates the Phospholipids Biosynthesis via the Pathways of Oxidative and Endoplasmic Reticulum Stress in the Intestine of Freshwater Teleost Yellow Catfish. Environ Sci Technol. 2018; 52(16):9206-9214. DOI: 10.1021/acs.est.8b02967. View

Norouzi S, Adulcikas J, Sohal S, Myers S . Zinc stimulates glucose oxidation and glycemic control by modulating the insulin signaling pathway in human and mouse skeletal muscle cell lines. PLoS One. 2018; 13(1):e0191727. PMC: 5786307. DOI: 10.1371/journal.pone.0191727. View

10.

Liu Y, Chen Y . High-efficiency thermal asymmetric interlaced PCR for amplification of unknown flanking sequences. Biotechniques. 2007; 43(5):649-50, 652, 654 passim. DOI: 10.2144/000112601. View

11.

Chen S, Wu K, Lv W, Chen F, Song C, Luo Z . Functional Analysis of Two Zinc (Zn) Transporters ( and ) Promoters and Their Distinct Response to and in the Regulation of Zn Metabolism. Int J Mol Sci. 2020; 21(17). PMC: 7503416. DOI: 10.3390/ijms21176135. View

12.

Basehoar A, Zanton S, Pugh B . Identification and distinct regulation of yeast TATA box-containing genes. Cell. 2004; 116(5):699-709. DOI: 10.1016/s0092-8674(04)00205-3. View

13.

Hoeke M, Heegsma J, Hoekstra M, Moshage H, Faber K . Human FXR regulates SHP expression through direct binding to an LRH-1 binding site, independent of an IR-1 and LRH-1. PLoS One. 2014; 9(2):e88011. PMC: 3912179. DOI: 10.1371/journal.pone.0088011. View

14.

Wei C, Luo Z, Hogstrand C, Xu Y, Wu L, Chen G . Zinc reduces hepatic lipid deposition and activates lipophagy via Zn/MTF-1/PPARα and Ca/CaMKKβ/AMPK pathways. FASEB J. 2018; :fj201800463. DOI: 10.1096/fj.201800463. View

15.

Wu C, Sun M, Liu L, Zhou G . The function of the protein tyrosine phosphatase SHP-1 in cancer. Gene. 2003; 306:1-12. DOI: 10.1016/s0378-1119(03)00400-1. View

16.

Zhang J, Hao J, Zhang Y, Wang Y, Li M, Miao H . Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in . J Lipid Res. 2017; 58(9):1845-1854. PMC: 5580898. DOI: 10.1194/jlr.M077198. View

17.

Bury N, Walker P, Glover C . Nutritive metal uptake in teleost fish. J Exp Biol. 2002; 206(Pt 1):11-23. DOI: 10.1242/jeb.00068. View

18.

Frank C, Makkonen H, Dunlop T, Matilainen M, Vaisanen S, Carlberg C . Identification of pregnane X receptor binding sites in the regulatory regions of genes involved in bile acid homeostasis. J Mol Biol. 2005; 346(2):505-19. DOI: 10.1016/j.jmb.2004.12.003. View

19.

Zou A, Magee N, Deng F, Lehn S, Zhong C, Zhang Y . Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis. J Biol Chem. 2018; 293(22):8656-8671. PMC: 5986206. DOI: 10.1074/jbc.RA117.001653. View

20.

Chen S, Lv W, Wu K, Chen G, Chen F, Song C . Dietary Nano-ZnO Is Absorbed via Endocytosis and ZIP Pathways, Upregulates Lipogenesis, and Induces Lipotoxicity in the Intestine of Yellow Catfish. Int J Mol Sci. 2021; 22(21). PMC: 8584588. DOI: 10.3390/ijms222112047. View